Veterinary World, EISSN: 2231-0916 REVIEW ARTICLE Available at www.veterinaryworld.org/Vol.11/November-2018/4.pdf Open Access The role of E3 ubiquitin ligase seven in absentia homolog in the innate immune system: An overview Ferbian Milas Siswanto1, I. Made Jawi2 and Bambang Hadi Kartiko1 1. Department of Biochemistry, Faculty of Health Science and Technology, Dhyana Pura University, Badung, Indonesia; 2. Department of Pharmacology, Faculty of Medicine, Udayana University, Denpasar, Indonesia. Corresponding author: Ferbian Milas Siswanto, e-mail: [email protected] Co-authors: IMJ: [email protected], BHK: [email protected] Received: 24-07-2018, Accepted: 03-10-2018, Published online: 07-11-2018 doi: 10.14202/vetworld.2018.1551-1557 How to cite this article: Siswanto FM, Jawi IM, Kartiko BH (2018) The role of E3 ubiquitin ligase seven in absentia homolog in the innate immune system: An overview, Veterinary World, 11(11): 1551-1557. Abstract The innate immune system has been considered as an ancient system and less important than the adaptive immune system. However, the interest in innate immunity has grown significantly in the past few years marked by the identification of Toll- like receptors, a member of pattern recognition receptors (PRRs). The PRRs are crucial for the identification of self- and non-self-antigen and play a role in the initiation of signaling events that activate the effective immune response. These sensor signals through interweaving signaling cascades which result in the production of interferons and cytokines as the effector of immune system. Ubiquitin and ubiquitin-like modifiers (UBLs) actively mediate the rapid and versatile regulatory processes that initiate the activation of the innate immune system cascade. The seven in absentia homolog (SIAH) is a potent RING finger E3 ubiquitin ligase that is known to involve in several stress responses, including hypoxia, oxidative stress, DNA damage stress, and inflammation. In this review, the role of SIAH will be discussed as an E3 ubiquitin ligase on the regulation of innate immune. Keywords: E3 ligase, innate immunity, regulation, seven in absentia homolog. Introduction biological processes, including different aspects of The innate immunity provides a first line of host immune functions [4]. Accumulating data suggest that defense against invading pathogens. The toll-like the ubiquitin and ubiquitin-like proteins (UBLs) are receptor (TLR) is one of the pattern recognition recep- emerging as the critical and versatile molecular signa- tures for orchestrating signaling networks emanating tors (PRRs) that sense pathogen-associated molecu- from the PRRs [5-7]. lar patterns which, in turn, initiate the immediate host Seven in absentia homolog (SIAH) protein fam- responses to restrict the pathogen infections. The ily is evolutionary conserved E3 ubiquitin ligases that pathogens binding with PRRs activate innate immune subject >30 substrates of proteins to degradation [8]. response through various signaling cascades and acti- SIAH limits its availability through self-ubiquitina- vate the pro-inflammatory transcription factors such tion and is an important regulator of pathways acti- as activator protein 1 (AP-1), nuclear factor-kappa B vated under hypoxia [9]. Under stress condition, p38 (NF-κB), and/or one or more members of the inter- mitogen-activated protein kinases (MAPK) and Akt feron (IFN) regulatory factor family which, in turn, pathways are activated and regulated the stabilization lead to the release of cytokines and IFNs [1,2]. In and activity of SIAH [10,11]. The study indicated that the meantime, adaptive immunity is initiated by the SIAH activity is regulated on infection by pathogens development of adaptive immune cells and the pro- and is important for the proper immune response [12]. duction of an antibody. Given the critical balances Furthermore, the research found that SIAH regulates of the PRR effectors to orchestrate the innate immu- tumor necrosis factor alpha (TNFα)-mediated NF-κB nity, they are subjected to multiple layers of positive signaling pathway [13]. However, there is no paper and negative protein post-translational modifications that has provided an integrative review on how SIAH (PTMs) [3]. Several PTMs such as phosphorylation, involves in the regulation of innate immune system. glycosylation, hydroxylation, acetylation, amidation, In this review, we will first introduce some key carboxylation, lipidation, sumoylation, and ubiquiti- concepts regarding the regulation of innate immunity nation dynamically modulate the affectivity of innate by ubiquitin system and then focus on the involve- immunity. Ubiquitination is important for many ment of SIAH ubiquitin ligase on innate immunity regulation. This paper highlights the role of its E3 Copyright: Siswanto, et al. Open Access. This article is distributed under the terms of the Creative Commons Attribution 4.0 ligase activity toward innate immune signaling. International License (http://creativecommons.org/licenses/ by/4.0/), which permits unrestricted use, distribution, and An Insight to the Ubiquitin System reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the The PTMs are required for the specific function, Creative Commons license, and indicate if changes were made. stability, degradation, and control of protein level in The Creative Commons Public Domain Dedication waiver (http:// creativecommons.org/publicdomain/zero/1.0/) applies to the data response to specific signals of the biological actions. made available in this article, unless otherwise stated. Ubiquitination is one of the PTMs characterized by Veterinary World, EISSN: 2231-0916 1551 Available at www.veterinaryworld.org/Vol.11/November-2018/4.pdf the conjugation of the 8.6-kD protein ubiquitin to degraded by the 26S proteasome as a part of protein target proteins, a process which marks a protein for turnover and homeostasis [24,25], while K63-linked proteolytic degradation by proteasomes. Ubiquitin ubiquitin chain and linear ubiquitin chain are often is prepared to bind to other proteins by the ATP- implicated in the regulation of signaling pathways and dependent ubiquitin-activating enzyme (E1) which the activation of kinases [16,26,27]. creates an active E1-bound ubiquitin and is deliv- In addition to the ubiquitination by three classes ered subsequently to a similar cysteine residue in the of enzymes (E1, E2, and E3), there is a group of active site of the ubiquitin-conjugating enzyme (E2). enzymes which acts to remove the ubiquitin from the Finally, a ubiquitin ligase (E3) binds to both the ubiq- proteasomes by an unknown mechanism. This group uitin-charged E2 and the substrate protein, leading to of enzymes is called the deubiquitinating enzymes the binding of ubiquitin to the target protein [14,15]. (DUBs), with a member of about 70 enzymes in Ubiquitinated proteins will bind to 26S proteasome human. The DUBs lead to the release of intact ubiqui- which marked protein for degradation by a 20S cat- tin for another cycle of attachment. After the deubiq- alytic subunit of the proteasome (Figure-1). The pro- uitination, proteins ratchet into the proteasome core tein abundance and subcellular distribution involved for peptide bond hydrolysis at three distinct active in almost every cellular process are regulated in this sites [28,29]. Other ubiquitinated proteins, such as model, with an increasingly clear role in the regula- plasma membrane proteins, are targeted to the vacuole tion of innate immunity [3,7,16,17]. degradation, and in this type of signaling, deubiquiti- There are two E1s, about 50 E2s, and >1000 E3 nation is a key to proper intracellular trafficking [30]. enzymes encoded in the human genome [18]. The E3 mostly plays a role in substrate specificity [19]. Regulation of Innate Immunity by Ubiquitin System Ubiquitin can undergo ubiquitination itself at the seven lysine residues (K6, K11, K27, K29, K33, K48, The regulation of the innate immune system or K63), building lysine-linked polyubiquitin chains by ubiquitin has been intensively reviewed in sev- or the N-terminal methionine (M1), leading to eral papers [3,7,16,17,31]. In general, the ubiquitin eight homotypic and multiple-mixed polyubiquitin and ubiquitin-like modifiers (UBLs) act by regulat- chains [20]. Alternatively, ubiquitin may be associ- ing the major PRR downstream. These major PRRs ated non-covalently with target proteins. The ubiqui- including TLRs reside in the plasma membrane and/ tin attached to substrate protein can be recognized by or endosome, NOD-like receptors (NLRs), RIG-like ubiquitin receptors that act as sequestering factor to receptors (RLRs), and cytosolic DNA sensors which direct the ubiquitinated protein to a specific intracel- are found in the cytoplasm [32]. lular site [21]. The classical example of ubiquitin-related TLR Subsequent ubiquitination can occur either as signaling regulation is the involvement of TNF recep- multi-monoubiquitination on different sites in the sub- tor-associated factor (TRAF). TLR activation, except strate protein or polyubiquitination on one site of the for TLR3, initiates the recruitment of adaptor protein substrate protein. The complexity of ubiquitination MyD88, IRAK4, and IRAK1 through its toll-inter- with the variation in the position, extent, and topol- leukin 1 receptor (TIR) homology domain. In turn, ogies of ubiquitin-ubiquitin linkages on a substrate IRAK4 activates IRAK-1 through